The goal of this project is to develop an understanding of the basic regulatory mechanisms in neurons which secrete peptide neurotransmitters, and through this understanding, develop novel pharmacotherapeutic approaches and agents for manipulating neuropeptidergic systems. Two investigations are ongoing. The first studies pre- and post-synaptic regulatory processes in peptidergic neurons which secrete multiple transmitters. The primary model under investigation is the opiomelanotropin-containing neuronal and endocrine system which secretes two peptides, Alpha-MSH and Beta-endorphin. These peptides are derived from a single gene and influence arousal processes through interactions with MSH receptors and analgesia through interactions with mu and delta opioid receptors. Our investigations indicate that there are extensive post-synaptic interactions between these co-transmitters and that the ratios of peptides secreted presynaptically can influence the post-synaptic action. We have studied the presynaptic regulation of synthesis of the different forms of POMC-derived peptides and found that regulation of prohormone and probably peptide processing enzyme occurs at the transcriptional level. These studies also indicate that effective antagonism of the actions of a particular peptidergic system requires the development of drugs which antagonize all the co-transmitters secreted. The second investigation is focused on determining if there is an endogenous peptide which interacts with the sigma opioid receptor. We have isolated a peptide that binds to sigma opioid sites and has similar behavioral and electrophysiological actions as sigma agonists such as phencyclidine (PCP). We have also developed the first antagonist for the sigma opioid receptor which effectively blocks the actions of PCP. This antagonist may be particularly useful for determining the roles of endogenous systems which secrete PCP-like peptides and may be clinically useful for treating PCP-induced psychoses, hallucinations resulting from therapeutic use of ketamine, a PCP-like anesthetic and, perhaps, functional psychoses.